ATP resynthesis occurs primarily through oxidative phosphorylation in mitochondria (>98%) and, to a small degree, through glycolysis (<2%). Oxidative phosphorylation requires O2 and H2. The O2 is delivered to the myocardium and consumed in the mitochondria to make H2O, and the H2 is from the metabolism of carbon fuels (mainly fatty acids, glucose, and lactate) and the generation of the reduced form of nicotinamide adenine dinucleotide (NADH). Pyruvate dehydrogenase (PDH) regulates the oxidation of glucose and lactate. The activity of PDH is inhibited by product inhibition from acetyl–coenzyme A and NADH. Also, PDH activity is inhibited when phosphorylated by PDH kinase and activated when dephosphorylated by PDH phosphatase. ATP is formed from ADP and inorganic phosphate with the use of H+ . Of importance is that the rates of ATP formation and breakdown depend on an adequate delivery of O2 to the myocardium, which is a function of myocardial blood flow and oxygenation of arterial blood. An increase in ATP breakdown in the myocardium, such as occurs when heart rate, systolic blood pressure, and contractility are increased (as during exercise), necessitates an increase in O2 delivery to the myocardium so that the mitochondria can generate sufficient ATP by oxidative phosphorylation to meet the demand for ATP. Thus the rate of myocardial O2 consumption is tightly linked to the work rate (or power) of the myocardium.
The heart is versatile in its use of substrates, and within certain limits, uptake of a particular substrate is directly proportional to its arterial concentration. The use of one substrate by the heart is also influenced by the presence or absence of other substrates. For example, the addition of lactate to the blood that perfuses a heart metabolizing glucose leads to a reduction in glucose uptake and vice versa. At normal blood concentrations, glucose and lactate are consumed at approximately equal rates.
In contrast, uptake of pyruvate is very low, as is its arterial concentration. For glucose, the threshold concentration is approximately 4 mmol/L. Below this blood level, no glucose is taken up by the myocardium. Insulin reduces the glucose threshold and increases the rate of glucose uptake by the heart. Cardiac utilization of lactate occurs in most circumstances; insulin does not affect its uptake by the myocardium. Under hypoxic conditions, glucose utilization is facilitated by an increase in the rate of transport across the myocardial cell wall. However, lactate cannot be metabolized by the hypoxic heart and is produced by the heart under anaerobic conditions. Associated with lactate production by the hypoxic heart is the breakdown of cardiac glycogen.
Of the total cardiac O2 consumption, only 35% to 40% can be accounted for by the oxidation of carbohydrate. Thus the heart derives the major part of its energy from the oxidation of noncarbohydrate sources: namely, esterified and nonesterified fatty acids, which account for approximately 60% of the myocardial O2 consumption in people in the postabsorptive state. Various fatty acids have different thresholds for myocardial uptake, but these
CHAPTER 16 Elements of Cardiac Function acids are generally used in direct proportion to their arterial concentration. Ketone bodies, especially acetoacetate, are readily oxidized by the heart, and they are a major source of energy in diabetic acidosis. As is true of carbohydrate substrates, use of a specific noncarbohydrate is influenced by the presence of other substrates, whether noncarbohydrate or carbohydrate. Therefore, within certain limits, the heart preferentially uses the substrate that is available in the largest concentration. The oxidation of amino acids makes a small contribution to myocardial energy expenditure.